10.10 : Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.

Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a diseased state. It also aids in controlling the levels of otherwise healthy proteins, which only have a short-lived function inside the cell under certain conditions.

One of the major protein degradation pathways active in eukaryotic cells is the ubiquitin-proteasome pathway. However, even this pathway is tightly regulated to only allow degradation of specific target proteins under certain conditions. Two of the most common regulatory mechanisms are the tight control of E3 ubiquitin ligase activity, and the unmasking degradation signals in the target proteins.

Humans have an estimated 600 or more E3 ubiquitin ligase genes, each of which can mediate their own target proteins' ubiquitination. However, E3 ligase activity is regulated via different mechanisms of action such as phosphorylation, or ligand binding. Similarly, the unmasking of degradation signals in the intracellular proteins is controlled by several different mechanisms such as phosphorylation, peptide bond cleavage, or protein subunit dissociation. Only when the E3 ligases recognize these normally hidden degradation signals can the target proteinbe ubiquitinated and degraded by the proteasome.